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WO2002058710A1 - Tagatose utilise en tant que nouveau traitement du syndrome metabolique x, de la dyslipidemie, et de la coronaropathie - Google Patents

Tagatose utilise en tant que nouveau traitement du syndrome metabolique x, de la dyslipidemie, et de la coronaropathie Download PDF

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Publication number
WO2002058710A1
WO2002058710A1 PCT/US2002/002008 US0202008W WO02058710A1 WO 2002058710 A1 WO2002058710 A1 WO 2002058710A1 US 0202008 W US0202008 W US 0202008W WO 02058710 A1 WO02058710 A1 WO 02058710A1
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WIPO (PCT)
Prior art keywords
tagatose
animal
cholesterol
study
subjects
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Ceased
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PCT/US2002/002008
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English (en)
Inventor
Thomas Donner
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University of Maryland Baltimore
University of Maryland College Park
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University of Maryland Baltimore
University of Maryland College Park
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Publication of WO2002058710A1 publication Critical patent/WO2002058710A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms

Definitions

  • Tagatose as a Novel Treatment for Metabolic Syndrome X, Dyslipidemia, and Coronary Artery Disease
  • This invention relates to the use of tagatose for the treatment of dyslipidemia, coronary artery disease, and metabolic syndrome X and for reducing the risk for heart attacks and restenosis after angioplasty.
  • Insulin resistance is defined as a decreased sensitivity in the peripheral tissues to a biological amount of insulin and was recognized as an important component of Type 2 diabetes mellitus over 50 years ago (Himsworth HP; Diabetes mellitus: Its differentiation into insulin sensitive and insulin insensitive types, Lancet, 1:127-130 (1936)).
  • the development of the euglycemic clamp technique (DeFronzo RA, et al.; Glucose clamp technique: A method for quantifying insulin secretion and resistance,
  • NIDDM obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease, Diabetes Care, 14:173-194 (1991); Lillioja S, et al.; Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus.
  • Proma Indians N. Engl. J. Med., 329:1988-92 (1993); Kahn CR; Banting Lecture: Insulin action, diabetogenes, and the cause of type II diabetes, Diabetes, 43: 1066-84 (1994)).
  • D-tagatose is a ketohexose sweetener which has many uses. Some examples of its uses are as follows: a treatment for hemophilia and anemia (U.S.
  • Patent 6,015,793 Levin to increase fertility in women and improve fetal development (U.S. Patent 6,225,452 Levin); to treat diabetes mellitus (U.S. Patent 5,447,917 Zehner et al.); to slow aging (U.S. Patent 5,356,879, Zehner et al.); and as a weight loss agent
  • D-tagatose When fed to rats, D-tagatose has no net metabolizable energy (Livesey G, et al.; D-Tagatose is a bulk sweetener with zero energy determined in rats, J. Nwtr., 126:1601-1609 (1996) and Levin GV, et al.; Sugar Substitutes: their energy values, bulk characteristics and potential health benefits, Am. J. Clin. Nutr. ,
  • D-tagatose tolerance test leads to no changes in plasma glucose or insulin levels.
  • Pre-treatment of type 2 DM subjects with doses of D- tagatose ranging from 10 to 75 g also attenuates the rise in plasma glucose following oral glucose in a dose-dependent manner (Donner TW, et al.; D-Tagatose, a novel hexose: acute effects on charbohydrate tolerance in subjects with and without type 2 diabeates, Diab. Obes. & Metab. , 285-292 (1999)).
  • Such beneficial cardiovascular effects include, but are not limited to, an increase in HDL-cholesterol levels, an increase in HDL- cholesterol levels along with a concurrent a reduction in LDL-cholesterol and triglyceride levels, a reduction in the risk for heart attacks, a reduction in the level of and risk for coronary artery disease, and a reduction in the risk for restenosis after angioplasty.
  • administration of 75 g of D-tagatose daily had no effect on blood cholesterol and lipid levels (Saunders JP, et al., Effects of acute and repeated oral doses of D-tagatose on plasma uric acid in normal and diabetic humans, Reg. Tox. Pharm.. 29(2 Pt 2 :S57-65 (1999)).
  • D-tagatose nor L-tagatose could be used as a treatment for this syndrome.
  • tagatose D-tagatose, L-tagatose, or a combination of both isomers
  • tagatose be administered to a mammal, including a human, to increase the level of HDL-cholesterol in the blood of that mammal, including a human.
  • tagatose D-tagatose, L-tagatose, or a combination of both isomers
  • tagatose be administered to a mammal, including a human, to decrease the level of LDL-cholesterol in the blood of that mammal, including a human.
  • tagatose D-tagatose, L-tagatose, or a combination of both isomers
  • tagatose be administered to a mammal, including a human, to decrease the level of triglycerides in the blood of that mammal, including a human.
  • tagatose D-tagatose, L-tagatose, or a combination of both isomers
  • tagatose be administered to a mammal, including a human, to treat metabolic syndrome X by reducing the animal's weight and dyslipidemia, and improving glucose intolerance.
  • tagatose be administered to a mammal, including a human, to treat metabolic syndrome X by reducing the animal's weight and dyslipidemia, and improving glucose intolerance.
  • tagatose D-tagatose, L-tagatose, or a combination of both isomers
  • tagatose be administered to a mammal, including a human, to reduce the risk for coronary artery disease in that mammal, including a human. It is also an object of this invention that the reduction in risk for coronary artery disease results from an increase in the HDL-cholesterol levels in the blood of the mammal, including human, by administration of tagatose.
  • tagatose D-tagatose, L-tagatose, or a combination of both isomers
  • tagatose be administered to a mammal, including a human, to reduce the risk for restenosis after angioplasty.
  • the reduction of risk for restenosis after angioplasty results from an increase in the HDL-cholesterol levels in the blood of the mammal, including human, by administration of tagatose.
  • tagatose D-tagatose, L-tagatose, or a combination of both isomers
  • tagatose be administered to a mammal, including a human, to reduce the risk for heart attacks in that mammal, including a human.
  • the reduction in risk for heart attacks results from an increase in the HDL-cholesterol levels in the blood of the mammal, including human, by administration of tagatose.
  • tagatose D-tagatose, L-tagatose, or a combination of both isomers
  • tagatose be administered to a mammal, including a human, to improve the cardiovascular health in that mammal, including a human.
  • the improvement of cardiovascular health results from an increase in the HDL-cholesterol levels in the blood of the mammal, including human, by administration of tagatose.
  • This invention involves the treatment of an animal, including human, having metabolic syndrome X by the administration of an effective amount of tagatose, i.e.,
  • This invention also involves the method for reducing the blood levels of LDL- cholesterol and/or for increasing the blood levels of HDL-cholesterol of an animal, including human, by the administration of an effective amount of tagatose, i.e. , D- tagatose, L-tagatose, or a mixture of the two isomers.
  • tagatose i.e. , D- tagatose, L-tagatose, or a mixture of the two isomers.
  • This invention also involves the method for reducing the risk for coronary artery disease in an animal, including human, by the administration of an effective amount of tagatose, i.e., D-tagatose, L-tagatose, or a mixture of the two isomers.
  • This invention also involves the method for reducing the risk for heart attack in an animal, including human, by the administration of an effective amount of tagatose, i.e., D-tagatose, L-tagatose, or a mixture of the two isomers.
  • This invention also involves the method for reducing the risk for restenosis after angioplasty in an animal, including human, by the administration of an effective amount of tagatose, i.e., D-tagatose, L-tagatose, or a mixture of the two isomers.
  • the tagatose may be administered to an animal, including human, in combination with a food or beverage, or taken separately in power, crystalline, or liquid form.
  • liquid or solid carriers such as water, starch, alcohol, or other non-toxic substances.
  • the tagatose (D-tagatose, L-tagatose, or a combination of D-tagatose and L-tagatose) is administered in the weight range of 100 mg/kg body weight/day to 2,000 mg/kg body weight/day.
  • the tagatose may be administered daily, every other day, or at other prescribed frequencies.
  • the daily dosage may be administered once, twice, three times or more per day. It may be administered in combination with other medications known to be suitable for use in the treatment of metabolic X syndrome, cardiovascular diseases, coronary artery disease, and dyslipidemia, or for medication to reduce LDL-cholesterol levels, or for the prevention of restenosis after angioplasty.
  • the third subject had glyburide 2.5 mg added at month 2.25 and had her troglitazone dose increased from 200 mg to 400 mg daily at month 4 of the treatment phase.
  • These three subjects were included in all outcome analyses, though subgroup analyses were done for glycosylated hemoglobin (GlyHb) and body weight parameters which are known to be affected by sulfonylureas and troglitazone.
  • GlyHb glycosylated hemoglobin
  • One subject had pravastatin added at month 7.3.
  • a lipid subgroup analysis was performed which excluded this subject and the one whose troglitazone was increased during the study.
  • a subgroup analysis was also performed on three subjects who had anti-hypertensive medications added during this study.
  • D-tagatose was prepared by Biospherics Incorporated (Beltsville, Maryland). Samples provided to subjects were >99% pure by HPLC analysis and were weighed and packaged in the University of Maryland, Baltimore Pharmacy School prior to administration. Study Protocol
  • Glycosylated hemoglobin (GlyHb) values were measured by the affinity column method (Helena Glyco-Tek, Beaumont, Texas) using well-known in the art- field techniques, which has a normal range of 4.4% ⁇ 7.7% and a mean intra-assay coefficient of variation of 2.95%. Insulin levels were measured by the Coates-A- count radioimmunoassay (RIA) method (Diagnostic Products Corporation, Los Angeles, California). Chemistry profiles and lipids were performed at the University of Maryland, Baltimore Chemistry Laboratory using well-known in the art field techniques. Results
  • D-tagatose was not found to have toxic effects on renal or hepatic functions, measures of which did not change during the twelve month treatment period. No other changes were observed in any of the other biochemical parameters tested during the treatment period.
  • D-tagatose was not felt to play a role in his myocardial infarction given numerous cardiovascular risk factors prior to study entry including low HDL-cholesterol levels, high triglycerides and LDL-cholesterol levels, mild diastolic hypertension, and his prior cerebrovascular accident. He was allowed to continue with the study after missing D-tagatose for one week while hospitalized, but was excluded thereafter from analyses for lipids and blood pressure because metoprolol and pravastatin were added to his drug regimen following his myocardial infarction.
  • baseline values are the average of readings taken two months before and immediately before the treatment period.
  • Kaplan showed that caloric restriction for three months in obese patients with type 2 DM leading to a 3 kg weight loss was associated with a 5.5 mg/dl increase in HDL- cholesterol (Kaplan RM, et al.; Prospective evaluation of HDL cholesterol changes after diet and physical conditioning programs for patients with type II diabetes mellitus, Diabetes Care, 8:343-348 (1985)). Wing found a more modest 2.5 mg/dl increase in HDL-cholesterol in obese type 2 DM patients only with weight loss exceeding 6.9 kg, after one year of caloric restriction and increases exercise (Wing
  • D-tagatose has previously been shown to blunt hyperglycemia significantly following oral glucose in a dose-dependant manner in subjects with type 2 DM (Donner TW, et al.; Diab. Obes. & Metab., L285-292 (1999)). Doses of D-tagatose as low as 10 g were efficacious. Subjects in this study received 15 g of D-tagatose with meals for 12 months. A number of limitations of this pilot study likely prevented a significant decline in GlyHb from being observed.
  • the third subject had 2.4% increase in GlyHb during the two month run-in period, and had a progressive deterioration in glycemic control for the next six months.
  • a 1% decrease in GlyHb was seen. Stable fasting glucose and insulin levels were observed during the treatment period while GlyHb levels were falling.
  • D-tagatose was improving postprandial hyperglycemia, an effect seen when D-tagatose is administered prior to oral GTT (Donner TW, et al.; Diab. Obes. & Metab., 1:285-292 (1999)).
  • a larger, placebo-controlled study is needed to confirm whether D-tagatose use in type 2 DM patients improves glycemic control, and to what degree better glycemic control correlates with weight loss.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'administration de tagatose (D-tagatose, L-tagatose, ou une combinaison des deux isomères) à des animaux, y compris aux humains, afin de traiter le syndrome métabolique X, de la dyslipidémie et de la coronaropathie. L'administration de tagatose (D-tagatose, L-tagatose, ou une combinaison des deux isomères) à des animaux, y compris des humains, réduit le risque d'attaques cardiaques, de coronaropathie, et de resténose suite à une angioplastie. Le tagatose améliore la santé cardiovasculaire et traite les maladies cardiovasculaires en augmentant les niveaux de cholestérol HDL. Le tagatose traite le syndrome métabolique X en réduisant le poids et la dyslipidémie de l'animal et en améliorant l'intolérance au glucose.
PCT/US2002/002008 2001-01-25 2002-01-25 Tagatose utilise en tant que nouveau traitement du syndrome metabolique x, de la dyslipidemie, et de la coronaropathie Ceased WO2002058710A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US26394901P 2001-01-25 2001-01-25
US60/263,949 2001-01-25

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WO2002058710A1 true WO2002058710A1 (fr) 2002-08-01

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1438055A4 (fr) * 2001-10-25 2006-11-22 Spherix Inc Utilisation de d-tagatose en tant qu'agent anti-film biologique
WO2008059625A1 (fr) * 2006-11-17 2008-05-22 National University Corporation Kagawa University Utilisation de la fonction de sucre rare en tant que promoteur de la migration de glucokinase depuis le noyau jusqu'au cytoplasme
WO2010054001A3 (fr) * 2008-11-04 2010-08-19 University Of Kentucky Research Foundation Compositions à base de d-tagatose et méthodes de prévention et de traitement de l'athérosclérose, du syndrome métabolique et de leurs symptômes
KR101475620B1 (ko) * 2013-08-13 2014-12-22 영남대학교 산학협력단 타가토스를 유효성분으로 함유하는 염증 또는 지방간 개선용 식의약품 첨가제
EP2756764A4 (fr) * 2011-09-15 2015-06-03 Cj Cheiljedang Corp Utilisation d'une composition édulcorante contenant un agent inhibiteur de glycolyse pour prévenir et réduire l'obésité

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4372948A (en) * 1980-04-11 1983-02-08 Kureha Kagaku Kogyo Kabushiki Kaisha Derivative of saccharide and physiologically active agent containing the same
US5591836A (en) * 1991-10-04 1997-01-07 The Procter & Gamble Company Cholesterol lowering compounds
US6015793A (en) * 1999-04-26 2000-01-18 Biospherics Incorporated Use of tagatose to enhance key blood factors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4372948A (en) * 1980-04-11 1983-02-08 Kureha Kagaku Kogyo Kabushiki Kaisha Derivative of saccharide and physiologically active agent containing the same
US5591836A (en) * 1991-10-04 1997-01-07 The Procter & Gamble Company Cholesterol lowering compounds
US6015793A (en) * 1999-04-26 2000-01-18 Biospherics Incorporated Use of tagatose to enhance key blood factors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LAERKE ET AL.: "D-tagatose has low small intestinal digestability but high large intestinal fementability in pigs 1,2", J. OF NUTR., vol. 129, no. 5, 3 May 1999 (1999-05-03), pages 1002 - 1009, XP002951121 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1438055A4 (fr) * 2001-10-25 2006-11-22 Spherix Inc Utilisation de d-tagatose en tant qu'agent anti-film biologique
WO2008059625A1 (fr) * 2006-11-17 2008-05-22 National University Corporation Kagawa University Utilisation de la fonction de sucre rare en tant que promoteur de la migration de glucokinase depuis le noyau jusqu'au cytoplasme
US20140336267A1 (en) * 2006-11-17 2014-11-13 National University Corporation Kagawa University Utilization of the function of rare sugar as promoter for the migration of glucokinase from nucleus to cytoplasm
JP5633952B2 (ja) * 2006-11-17 2014-12-03 松谷化学工業株式会社 Ｄ−プシコースを有効成分とするグルコキナーゼの核から細胞質への移行の促進剤
WO2010054001A3 (fr) * 2008-11-04 2010-08-19 University Of Kentucky Research Foundation Compositions à base de d-tagatose et méthodes de prévention et de traitement de l'athérosclérose, du syndrome métabolique et de leurs symptômes
US20110263518A1 (en) * 2008-11-04 2011-10-27 University Of Kentucky Research Foundation D-Tagatose-Based Compositions and Methods for Preventing and Treating Atherosclerosis, Metabolic Syndrome, and Symptoms Thereof
RU2484827C2 (ru) * 2008-11-04 2013-06-20 Юниверсити Оф Кентукки Рисерч Фаундэйшн Композиции на основе d-тагатозы и способы предупреждения и лечения атеросклероза, метаболического синдрома и их симптомов
US9060962B2 (en) * 2008-11-04 2015-06-23 University Of Kentucky Research Foundation D-tagatose-based compositions and methods for preventing and treating atherosclerosis, metabolic syndrome, and symptoms thereof
EP2756764A4 (fr) * 2011-09-15 2015-06-03 Cj Cheiljedang Corp Utilisation d'une composition édulcorante contenant un agent inhibiteur de glycolyse pour prévenir et réduire l'obésité
KR101475620B1 (ko) * 2013-08-13 2014-12-22 영남대학교 산학협력단 타가토스를 유효성분으로 함유하는 염증 또는 지방간 개선용 식의약품 첨가제

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